Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway
Background/Aims: Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Cell Physiol Biochem Press GmbH & Co KG
2018-09-01
|
| Series: | Cellular Physiology and Biochemistry |
| Subjects: | |
| Online Access: | https://www.karger.com/Article/FullText/493655 |
| _version_ | 1828900524505694208 |
|---|---|
| author | Xiaoye Fan Lidong Wang Jingbo Huang Hongming Lv Xuming Deng Xinxin Ci |
| author_facet | Xiaoye Fan Lidong Wang Jingbo Huang Hongming Lv Xuming Deng Xinxin Ci |
| author_sort | Xiaoye Fan |
| collection | DOAJ |
| description | Background/Aims: Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in vivo. Methods: C57BL/6 mice were treated with APAP or APAP+Pts. HepG2 cells were used to further explore the underlying mechanisms in vitro. The effects of Pts on hepatotoxicity were measured by commercial kits, Hematoxylin and Eosin (H&E) straining, TUNEL assay, Western blot analysis, and Flow cytometry assay. Results: In vivo, Pts treatment effectively protected against APAP-induced severe liver injury by decreasing the lethality rate, the serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, liver histological injury, liver malondialdehyde (MDA) formation and myeloperoxidase (MPO) levels and by increasing liver glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, in Pts-treated mice, the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was activated; however, APAP-induced c-Jun NH2-terminal kinase (JNK) activation, mitochondrial Bcl-2 Associated X Protein (Bax) translocation, apoptosis-inducing factor (AIF) levels and cytochrome c release were attenuated. In vitro, Pts was found to reverse hydrogen peroxide (H2O2) -induced cytotoxicity, reactive oxygen species (ROS) production and apoptosis that depended on Nrf2 activation. Moreover, Pts induced a dose-dependent increase in the phosphorylation of AMP-activated protein kinase (AMPK), serine/threonine kinase (Akt), and glycogen synthase kinase 3β (GSK3β) in HepG2 cells. Moreover, Pts protect against APAP or H2O2-induced toxicity were effectively attenuated or abolished in HepG2 Nrf2-/- cells and Nrf2-/- mice. Conclusion: Our data suggest that Pts protects against APAP-induced toxicity by activating Nrf2 via the AMPK/Akt/GSK3β pathway. |
| first_indexed | 2024-12-13T15:48:01Z |
| format | Article |
| id | doaj.art-d9a9f3c1448647029693ba4ef2cff7cd |
| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-12-13T15:48:01Z |
| publishDate | 2018-09-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-d9a9f3c1448647029693ba4ef2cff7cd2022-12-21T23:39:37ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782018-09-014951943195810.1159/000493655493655Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β PathwayXiaoye FanLidong WangJingbo HuangHongming LvXuming DengXinxin CiBackground/Aims: Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in vivo. Methods: C57BL/6 mice were treated with APAP or APAP+Pts. HepG2 cells were used to further explore the underlying mechanisms in vitro. The effects of Pts on hepatotoxicity were measured by commercial kits, Hematoxylin and Eosin (H&E) straining, TUNEL assay, Western blot analysis, and Flow cytometry assay. Results: In vivo, Pts treatment effectively protected against APAP-induced severe liver injury by decreasing the lethality rate, the serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, liver histological injury, liver malondialdehyde (MDA) formation and myeloperoxidase (MPO) levels and by increasing liver glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, in Pts-treated mice, the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was activated; however, APAP-induced c-Jun NH2-terminal kinase (JNK) activation, mitochondrial Bcl-2 Associated X Protein (Bax) translocation, apoptosis-inducing factor (AIF) levels and cytochrome c release were attenuated. In vitro, Pts was found to reverse hydrogen peroxide (H2O2) -induced cytotoxicity, reactive oxygen species (ROS) production and apoptosis that depended on Nrf2 activation. Moreover, Pts induced a dose-dependent increase in the phosphorylation of AMP-activated protein kinase (AMPK), serine/threonine kinase (Akt), and glycogen synthase kinase 3β (GSK3β) in HepG2 cells. Moreover, Pts protect against APAP or H2O2-induced toxicity were effectively attenuated or abolished in HepG2 Nrf2-/- cells and Nrf2-/- mice. Conclusion: Our data suggest that Pts protects against APAP-induced toxicity by activating Nrf2 via the AMPK/Akt/GSK3β pathway.https://www.karger.com/Article/FullText/493655Pterostilbene AcetaminophenHepatotoxicityNrf2AMPK/Akt/GSK3β pathway |
| spellingShingle | Xiaoye Fan Lidong Wang Jingbo Huang Hongming Lv Xuming Deng Xinxin Ci Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway Cellular Physiology and Biochemistry Pterostilbene Acetaminophen Hepatotoxicity Nrf2 AMPK/Akt/GSK3β pathway |
| title | Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway |
| title_full | Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway |
| title_fullStr | Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway |
| title_full_unstemmed | Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway |
| title_short | Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway |
| title_sort | pterostilbene reduces acetaminophen induced liver injury by activating the nrf2 antioxidative defense system via the ampk akt gsk3β pathway |
| topic | Pterostilbene Acetaminophen Hepatotoxicity Nrf2 AMPK/Akt/GSK3β pathway |
| url | https://www.karger.com/Article/FullText/493655 |
| work_keys_str_mv | AT xiaoyefan pterostilbenereducesacetaminopheninducedliverinjurybyactivatingthenrf2antioxidativedefensesystemviatheampkaktgsk3bpathway AT lidongwang pterostilbenereducesacetaminopheninducedliverinjurybyactivatingthenrf2antioxidativedefensesystemviatheampkaktgsk3bpathway AT jingbohuang pterostilbenereducesacetaminopheninducedliverinjurybyactivatingthenrf2antioxidativedefensesystemviatheampkaktgsk3bpathway AT hongminglv pterostilbenereducesacetaminopheninducedliverinjurybyactivatingthenrf2antioxidativedefensesystemviatheampkaktgsk3bpathway AT xumingdeng pterostilbenereducesacetaminopheninducedliverinjurybyactivatingthenrf2antioxidativedefensesystemviatheampkaktgsk3bpathway AT xinxinci pterostilbenereducesacetaminopheninducedliverinjurybyactivatingthenrf2antioxidativedefensesystemviatheampkaktgsk3bpathway |